The schizophrenia- and autism-associated gene, transcription factor 4 regulates the columnar distribution of layer 2/3 prefrontal pyramidal neurons in an activity-dependent manner.
The schizophrenia- and autism-associated gene, transcription factor 4 regulates the columnar distribution of layer 2/3 prefrontal pyramidal neurons in an activity-dependent manner.
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DOI：
10.1038/mp.2017.37
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发表时间：
2018-03
影响因子：
11
通讯作者：
Maher BJ
中科院分区：
文献类型：
--
作者：
Page SC;Hamersky GR;Gallo RA;Rannals MD;Calcaterra NE;Campbell MN;Mayfield B;Briley A;Phan BN;Jaffe AE;Maher BJ
大脑的层状和柱状组织的破坏与几种精神疾病有关。在这里，我们显示在子宫内获得功能的精神病风险基因转录因子4（TCF 4）严重破坏了内侧前额叶皮层（mPFC）的柱状组织的转录和活动依赖的方式。这种形态学表型通过以钙依赖性方式共表达TCF 4加钙调蛋白以及通过共表达内向整流钾通道（Kir2.1）抑制神经元兴奋性而被拯救。这是第一次，我们表明，NMDA受体依赖的Ca 2+瞬变是有益的minicolumn组织，因为Crispr/Cas9介导的突变的NMDA受体拯救TCF 4依赖的形态表型。此外，我们证明了精神病风险基因TCF 4的转录调控增强了NMDA受体依赖的早期网络振荡。我们的新发现表明，TCF 4依赖的转录指导正确形成的前额叶皮质微柱通过调节基因的表达参与早期自发神经元活动，因此我们的研究结果提供了深入了解TCF 4相关的精神疾病的潜在病理生理机制。
Disruption of the laminar and columnar organization of the brain is implicated in several psychiatric disorders. Here, we show in utero gain-of-function of the psychiatric risk gene transcription factor 4 (TCF4) severely disrupts the columnar organization of medial prefrontal cortex (mPFC) in a transcription- and activity-dependent manner. This morphological phenotype was rescued by co-expression of TCF4 plus calmodulin in a calcium-dependent manner and by dampening neuronal excitability through co-expression of the inwardly rectifying potassium channel (Kir2.1). For the first time, we show that NMDA receptor-dependent Ca2+ transients are instructive to minicolumn organization because Crispr/Cas9-mediated mutation of NMDA receptors rescued TCF4-dependent morphological phenotypes. Furthermore, we demonstrate that the transcriptional regulation by the psychiatric risk gene TCF4 enhances NMDA receptor-dependent early network oscillations. Our novel findings indicate that TCF4-dependent transcription directs the proper formation of prefrontal cortical minicolumns by regulating the expression of genes involved in early spontaneous neuronal activity, and thus our results provides insights into potential pathophysiological mechanisms of TCF4 associated psychiatric disorders.
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影响因子：
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通讯作者：
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